Multi-trait genome-wide analysis identified novel risk loci and candidate drugs for heart failure

Abstract

AbstractHeart failure (HF) is a common cardiovascular disease that poses significant morbidity and mortality risks. While genome-wide association studies reporting on HF abound, its genetic etiology is not well understood due to its inherent polygenic nature. Moreover, these genetic insights have not been completely translated into effective strategies for the primary treatment of HF. In this study, we conducted a large-scale integrated multi-trait analysis using European-ancestry GWAS summary statistics of coronary artery disease and HF, involving near 2 million samples to identify novel risk loci associated with HF. 72 loci were newly identified with HF, of which 44 were validated in the replication phase. Transcriptome association analysis revealed 215 HF risk genes, includingEDNRAandFURIN. Pathway enrichment analysis of risk genes revealed their enrichment in pathways closely related to HF, such as response to endogenous stimulus (adjusted P = 8.83×10-3), phosphate-containing compound metabolic process (adjusted P = 1.91×10-2). Single-cell analysis indicated significant enrichments of these genes in smooth muscle cells, fibroblast of cardiac tissue, and cardiac endothelial cells. Additionally, our analysis of HF risk genes identified 74 potential drugs for further pharmacological evaluation. These findings provide novel insights into the genetic determinants of HF, highlighting new genetic loci as potential interventional targets to HF treatment, with significant implications for public health and clinical practice.